Lapatinib (Tykerb) is a dual kinase inhibitor that is available as an oral medicine for the treatment of patients with breast cancer. It exerts its action by inhibiting the HER2/neu and epidermal growth factor receptor pathways.
Lapatinib (Tykerb) Uses:
-
Breast cancer:
- Treatment of human epidermal growth receptor type 2 (HER2) overexpressing advanced or metastatic breast cancer (in combination with capecitabine) in patients who have received prior therapy (with an anthracycline, a taxane, and trastuzumab)
- HER2 overexpressing hormone receptor-positive metastatic breast cancer in postmenopausal women where hormone therapy is indicated (in combination with letrozole)
- Limitations of use:
- Patients should have disease progression on trastuzumab prior to initiation of treatment with lapatinib in combination with capecitabine.
-
Off Label Use of Lapatinib in Adults:
- HER2 overexpressing metastatic breast cancer (in combination with trastuzumab) with progression on prior trastuzumab-containing therapy
- HER2 overexpressing metastatic breast cancer with brain metastases (in combination with capecitabine)
Lapatinib (Tykerb) Dose in Adults:
Lapatinib (Tykerb) Dose in the treatment of metastatic, HER2+ Breast cancer (with a prior anthracycline, taxane, and trastuzumab therapy):
- Oral:
- 1,250 mg OD (in combination with capecitabine) until disease progression or unacceptable toxicity
Lapatinib (Tykerb) Dose in the treatment of metastatic, HER2+ Breast cancer (hormonal therapy indicated):
- Oral:
- 1,500 mg once daily (in combination with letrozole) until disease progression
Lapatinib (Tykerb) Dose when used as a first-line therapy metastatic, HER2+ Breast cancer with brain metastases (off-label):
- Oral:
- 1,250 mg once daily (in combination with capecitabine) until disease progression or unacceptable toxicity.
Lapatinib (Tykerb) dose in the treatment of metastatic, HER2+ Breast cancer with progression on prior trastuzumab therapy (off label):
- Oral:
- 1,000 mg once daily (in combination with trastuzumab)
- Missed doses: If a dose is missed, resume with the next scheduled daily dose; do not double the dose the next day.
Lapatinib (Tykerb) Dosage adjustment for concomitant CYP3A4 inhibitors/ inducers:
-
CYP3A4 inhibitors:
- Avoid the use of concomitant strong CYP3A4 inhibitors.
- If concomitant use cannot be avoided, consider reducing lapatinib to 500 mg once a day with careful monitoring.
- When a strong CYP3A4 inhibitor is discontinued, allow ~1 week to elapse prior to adjusting the lapatinib dose upward.
-
CYP3A4 inducers:
- Avoid the use of concomitant strong CYP3A4 inducers.
- If concomitant use cannot be avoided, consider gradually titrating lapatinib from 1,250 mg once a day up to 4,500 mg daily (in combination with capecitabine) or from 1,500 mg once a day up to 5,500 mg daily (in combination with letrozole), based on tolerability and with careful monitoring.
- If the strong CYP3A4 enzyme inducer is discontinued, reduce the lapatinib dose to the indicated dose.
Use in Children:
Not indicated.
Lapatinib Pregnancy Risk Category: D
- Based on data from animal reproduction studies and the mechanism of action, it is possible that in utero lapatinib exposure can cause harm to fetuses.
- Females with reproductive potential and pregnant females should be aware of the possible risk to their fetus.
- The European Society for Medical Oncology's guidelines for treating cancer in pregnancy recommend that pregnant patients with HER-2 positive diseases delay treatment with HER-2 targeted drugs until after the delivery.
- Before lapatinib can be initiated, pregnant women should be assessed.
- Effective contraception should be used by females with reproductive potential and male patients who have female partners with reproductive potential.
Use of lapatinib during lactation
- It is unknown if breast milk contains lapatinib.
- Breastfeeding can cause serious adverse reactions in breastfed babies.
- This is why lactating mothers should not breastfeed during lapatinib treatment and for at least one week after the last dose.
Lapatinib (Tykerb) Dose in Kidney Disease:
- No dosage adjustments provided in the manufacturer’s labeling (has not been studied).
- However, due to minimal renal elimination (<2%), dosage adjustments may not be necessary.
Lapatinib (Tykerb) Dose in Liver disease:
- Mild or moderate preexisting impairment (Child-Pugh class A or B):
- No dosage adjustments provided in the manufacturer’s labeling.
- Severe preexisting impairment (Child-Pugh class C):
- The following adjustments should be considered (and are predicted to normalize the AUC), however, there are no clinical data associated with the adjustments.
- In combination with capecitabine:
- Reduce dose from 1,250 mg OD to 750 mg OD.
- In combination with letrozole:
- Reduce dose from 1,500 mg OD to 1,000 mg OD.
- Severe hepatotoxicity during treatment:
- Discontinue permanently (do not rechallenge).
Common Side Effects of Lapatinib (Tykerb):
-
Central Nervous System:
- Fatigue
- Headache
-
Dermatologic:
- Palmar-Plantar Erythrodysesthesia
- Skin Rash
- Alopecia
- Xeroderma
- Pruritus
- Nail Disease
-
Gastrointestinal:
- Diarrhea
- Nausea
- Vomiting
- Mucositis
- Stomatitis
- Anorexia
- Dyspepsia
-
Hematologic & Oncologic:
- Decreased Hemoglobin
- Decreased Neutrophils
- Decreased Platelet Count
-
Hepatic:
- Increased Serum Aspartate Aminotransferase
- Increased Serum Alanine Aminotransferase
- Increased Serum Bilirubin
-
Neuromuscular & Skeletal:
- Asthenia
- Limb Pain
- Back Pain
-
Respiratory:
- Dyspnea
- Epistaxis
Less Common Side Effects of Lapatinib (Tykerb):
-
Cardiovascular:
- Decreased left ventricular ejection fraction
-
Central nervous system:
- Insomnia
Contraindications to Lapatinib (Tykerb):
- Hypersensitivity to lapatinib and any component of the formulation.
Warnings and precautions
-
Cardiotoxicity
- Reports of a decrease in left ventricular Ejection Fraction (LVEF), have been made (usually within the first three months of treatment).
- It is recommended to conduct periodic and baseline LVEF assessments.
- If the patient is not symptomatic and the LVEF >=grade 2 has been reduced, the doctor may interrupt treatment.
- Avoid using this medication in conditions that could impair left-ventricular function or in patients who have had (or are predisposed to) left ventricular dysfunction.
- The American Heart Association has stated that lapatinib may cause reversible myocardial toxicities or worsen underlying myocardial dysfunction in a scientific statement.
-
Dermatologic toxicities:
- Use has been associated with severe cutaneous reactions.
- If life-threatening dermatologic reactions such as blisters, skin lesions, or progressive skin rash, discontinue treatment.
-
Diarrhea
- Diarrhea can be severe and/or fatal. It usually occurs within six days.
- Diarrhea can be managed by early intervention. Patients should immediately report any changes in their bowels.
- Apply antidiarrheal agent after first stool is unformed
- If severe diarrhea is present, you may need to hydrate, electrolyte, and antibiotics (if the duration is greater than 24 hours, fever, grade 3/4 neutropenia, or fever), as well as treatment interruption, dose reduction or discontinuation.
-
Hepatotoxicity: [US Boxed Warning]
- Hepatotoxicity has been reported in patients treated with lapatinib. It can be serious and/or fatal.
- The onset of symptoms can occur as soon as treatment is initiated, but it could take several months before they appear.
- Monitor transaminases and bilirubin and alkalinephosphatase at baseline and every 4 to6 weeks during treatment and as clinically necessary
- If severe liver damage occurs during treatment, discontinue the medication and do not re-initiate.
-
Toxicity in the lungs:
- Pneumonitis and interstitial lung disease (ILD), have been reported with lapatinib monotherapy or combination chemotherapy.
- Check for any pulmonary symptoms that may indicate ILD, or pneumonitis.
- Stop treating grade 3 or higher pulmonary symptoms (eg dry cough, dyspnea) that are indicative of ILD/pneumonitis.
-
QTC extension:
- Longevity of QTC has been observed to be concentration-dependent
- Patients with a history QTC prolongation or taking medications that prolong the QT interval should be cautious.
- It is important to consider both the 12-lead ECG and the baseline ECG.
- Before and during treatment, correct electrolyte (potassium-, calcium-, and magnesium) anomalies
- Combining other drugs with QTC prolonging drugs can increase the risk for potentially fatal arrhythmias.
-
Hepatic impairment
- Patients with hepatic impairment should be cautious
- Patients with severe (Child Puugh class C) hepatic impairment should consider dose reductions.
Lapatinib: Drug Interaction
|
Aprepitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
ARIPiprazole |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. |
|
Bosentan |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Brentuximab Vedotin |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. |
|
Celiprolol |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. |
|
Clofazimine |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
CYP3A4 Inducers (Moderate) |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
CYP3A4 Inhibitors (Moderate) |
May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). |
|
Deferasirox |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Dofetilide |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. |
|
Duvelisib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Erdafitinib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Erdafitinib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Erdafitinib |
May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. |
|
Everolimus |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. |
|
Flibanserin |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. |
|
Fosaprepitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Fosnetupitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Haloperidol |
QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTcprolonging effect of Haloperidol. |
|
Ivosidenib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Larotrectinib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Larotrectinib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. |
|
Naldemedine |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. |
|
Naloxegol |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. |
|
Netupitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
NiMODipine |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. |
|
Palbociclib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
P-glycoprotein/ABCB1 Inhibitors |
May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). |
|
P-glycoprotein/ABCB1 Substrates |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. |
|
Prucalopride |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. |
|
QT-prolonging Agents (Highest Risk) |
QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. |
|
Ranolazine |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. |
|
Ranolazine |
May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. |
|
RifAXIMin |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. |
|
Sarilumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Silodosin |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. |
|
Siltuximab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Simeprevir |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Talazoparib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. |
|
Talazoparib |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. |
|
Tegaserod |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. |
|
Tocilizumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Risk Factor D (Consider therapy modification) |
|
|
Afatinib |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. |
|
Alpelisib |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. |
|
Betrixaban |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. |
|
Bilastine |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. |
|
Cladribine |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. |
|
Colchicine |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. |
|
Dabigatran Etexilate |
|
|
Dabrafenib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). |
|
DOXOrubicin (Conventional |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. |
|
Edoxaban |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. |
|
Lefamulin |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. |
|
Lemborexant |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. |
|
Lomitapide |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. |
|
Lorlatinib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. |
|
Stiripentol |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. |
|
Triazolam |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant weak CYP3A4 inhibitors. |
|
Ubrogepant |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (if needed) of ubrogepant should be limited to 50 mg. |
|
Venetoclax |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. |
|
Risk Factor X (Avoid combination) |
|
|
Conivaptan |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
CYP3A4 Inducers (Strong) |
May decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. |
|
CYP3A4 Inhibitors (Strong) |
May increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. |
|
DexAMETHasone (Systemic |
May decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. |
|
Fusidic Acid (Systemic) |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Grapefruit Juice |
May increase the serum concentration of Lapatinib. |
|
Idelalisib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Lasmiditan |
May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. |
|
PAZOPanib |
Lapatinib may enhance the QTc-prolonging effect of PAZOPanib. Lapatinib may increase the serum concentration of PAZOPanib. |
|
Pimozide |
CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. |
|
St John's Wort |
May decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. |
|
Topotecan |
BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. |
|
Topotecan |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. |
|
VinCRIStine (Liposomal) |
P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). |
Monitoring parameters:
- LVEF (baseline and periodic)
- CBC with differential
- Liver function tests, including transaminases, bilirubin, and alkaline phosphatase (baseline and every 4-6 weeks during treatment)
- Electrolytes including calcium, potassium, magnesium
- Monitor for fluid retention
- ECG monitoring if at risk for QTc prolongation
- Symptoms of ILD or pneumonitis
- Monitor for diarrhea and dermatologic toxicity
- Evaluate pregnancy status in females of reproductive potential prior to therapy.
How to administer Lapatinib (Tykerb)?
- Administer once daily, on an empty stomach, 1 hour before or 1 hour after a meal.
- Take the full dose at the same time each day; dividing dose throughout the day is not recommended.
Note:
- For combination treatment with capecitabine, capecitabine should be administered in 2 doses (approximately 12 hours apart) and taken with food or within 30 minutes after a meal.
Mechanism of action of Lapatinib (Tykerb):
- Inhibitor of Tyrosine Kinase (dual-kinase).
- By binding to tyrosine kinase and blocking phosphorylation, it inhibits EGFR and HER2 (ErbB1), activating downstream messengers (Erk1/2, Akt), and regulating cell proliferation and survival in ErbB2- and ErbB2-expressing tumors.
- Combination therapy with lapatinib or endocrine treatment may be able to overcome endocrine resistance in HER2+ or hormone receptor-positive diseases.
Absorption:
- Incomplete and variable
Protein binding:
- >99% to albumin and alpha -acid glycoprotein
Metabolism:
- Hepatic; extensive via CYP3A4 and 3A5, and to a lesser extent via CYP2C19 and 2C8 to oxidized metabolites
Half-life elimination:
- ~24 hours
Time to peak, plasma:
- ~4 hours (Burris 2009)
Excretion:
- Feces (27% as unchanged drug; range 3% to 67%)
- urine (<2%)
International Brands of Lapatinib:
- Tykerb
- Tyverb
Lapatinib Brand Names in Pakistan:
No Brands Available in Pakistan.
